PROJECT SUMMARY/ABSTRACT The farnesoid X receptor (FXR) is an adopted nuclear receptor activated by bile acids. In the ileum, FXR activation induces the production and secretion of fibroblast growth factor 15 (FGF15), mouse orthologue of human FGF19, into hepatic portal circulation. In the liver, FGF15/19 binds its receptor FGFR4 and acts as a negative feedback factor down-regulating genes involved in the synthesis of bile acids. In addition to its characterized effects on bile acid homeostasis, it is becoming apparent that FGF15 may be a pro-fibrotic factor in the liver. In a recent study and in our preliminary evidence, Fgf15 knockout (Fgf15-/-) mice were protected against both carbon tetrachloride (CCl4) and high fat diet induced liver fibrosis. The central hypothesis is that FGF15 promotes liver fibrosis by both direct and indirect pathways: direct activation of FGF15/19 signaling in HSCs and reduction of FXR activation by decreasing bile acid levels. Data from this study will have multiple important implications and therapeutic applications for the treatment of hepatic fibrosis as compounds targeting both FXR and FGF15/19 pathways are currently in late phase clinical trials for many forms of liver diseases and cancers. Aim 1. Comprehensively assess the effects of FGF19 and FXR activation on the human stellate cell line LX-2. In order to determine the direct effects FGF19 and FXR on HSC phenotype, LX-2 cells will be cultured with and without recombinant FGF19 and obeticholic acid (OCA), a FXR synthetic ligand. LX-2 cells and recombinant FGF19 were selected for this aim as they are of human origin and thus have greater relevance to human health. The findings from this in vitro study will provide the basis for identifying the in vivo mechanism(s) by which FGF15/19 and FXR signaling regulates HSC function during the development of hepatic fibrosis. Aim 2. Differentiate the effects of FGF15 and FXR on HSC activation in vivo using the CCl4 hepatic fibrosis model in conjunction with bile sequestration. Fgf15-/-, Fgf15 transgenic, and WT mice will be treated with CCl4 with or without cholestyramine. This proposed study is timely and significant to provide a mechanistic insight into the differentiated effect of FGF15/19 and FXR on HSC activation and proliferation. The proposed study is also novel both conceptually (effect of FGF15/19 on liver fibrosis) and technically (novel Fgf15 transgenic mice).